Interleukin-6 (IL-6) and C-reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case-control study to evaluate the relation between prediagnostic levels of IL-6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL-6 (-174 G/C) polymorphism in relation to circulating levels of IL-6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL-6 nor CRP plasma levels varied significantly by IL-6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL-6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL-6 and BMI on prostate cancer incidence (p(interaction) < 0.01). Increasing IL-6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL-6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (p(trend) = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL-6 level. Our study suggests that IL-6 may potentially be involved in the development or progression of prostate cancer.